Microglia, immune cells in the brain, play major immunological/inflammatory roles as brain macrophage in the central nerve system (CNS). The origin of resident microglia proved to be from primitive myeloid progenitors (primitive macrophage) that arise in the yolk sac before embryonic day 8 (1). Resident microglia form as a ramified type (called ramified microglia), whose branches constantly move and survey the microenvironment under physiological conditions in the CNS (2), and once activated, shift the form of an ameboid type, phagocytose, and release various mediators such as inflammatory cytokines (3-5). Microglia are suggested to contribute to the pathophysiology of various neurological and psychiatric disorders (6-8). NasuHakola disease (NHD) is a very rare autosomal recessive disorder, initially reported in Finland and Japan (9, 10), which is believed to be caused by microglial dysfunction. Until now, only about 200 cases have been reported worldwide and the majority of cases are in the Finnish and Japanese populations (11). NHD is characterized by formation of multifocal bone cysts and progressive early-onset dementia with various psychiatric symptoms including personality changes (11, 12), caused by mutations of DNAX-activation protein 12 (DAP12) (13) or triggering receptor expressed on myeloid cells 2 (TREM2) (14), both of which are expressed in human microglia. A rodent brain study showed that DAP12 is expressed only in microglia and deletion of DAP12 induces synaptic impairments possibly due to microglial dysfunction (15). A human postmortem study has revealed the absence of DAP12 expression on ramified microglia in brains of NHD (16).
Above-mentioned reports have strongly supported that human microglial cells maladaptively contribute to a variety of neurological and psychiatric disorders including NHD, while the dynamic microglial dysfunction in human brain have not been clarified. The most significant limitation in human brain research is the difficulty in obtaining living brain cells including microglial cells from living human brains based on ethical and technical perspectives. To solve this limitation, alternative methods have long been warranted. Presently, human neuronal cells can be established from somatic cells (not from the brain) such as skin fibroblasts by utilizing the gene-modification technique of induced pluripotent stem (iPS) cells (17, 18). In addition, recently, neuronal cells are more easily established from direct conversion of human skin fibroblasts, called induced neuronal (iN) cells (19-21). Novel methods of establishing ramified microglia from human somatic cells are strongly warranted, based on iPS or direct conversion techniques, while none have yet been reported.